Atherosclerosis is a complex and chronic disease involving the gradual accumulation of lipids, collagen, elastic fibers and proteoglycans in the arterial wall. Current methods of managing atherosclerosis include a low-fat diet, exercise and various cholesterol-lowering drugs. Although these methods can significantly retard the progression of atherosclerosis, they are not entirely satisfactory.
Heparin sulfate proteoglycans (HSPGs) produced by vascular endothelium are believed to retard the migration, multiplication and phenotypic transition of vascular smooth muscle cells, events which play a central role in the atherogenic process, and to maintain an anticoagulant luminal surface by binding and activating antithrombin III (Clowes et al., Nature, 265:625-626, 1977; Guyton et al., Circ. Res., 46:625-634, 1980; Edelman et al., Proc. Natl. Acad. Sci. U.S.A., 87:3773-3777, 1990).
Various silicon compounds administered orally or parenterally have been demonstrated to inhibit cholesterol-induced intimal hyperplasia (atherosclerosis) in rabbits (Loeper et al., Athersclerosis, 33:397-408, 1979; Loeper et al., in Biochemistry of Silicon and Related Problems, Plenum Press, New York, 1978, pp 281-296; Garson et al., J. Pharm. Sci., 60:1113-1127, 1971). The injection or ingestion of nutritionally available silicon compounds (i.e. monomethyltrisilanol, lysine silicate, sodium silicate) prevented the characteristic intimal thickening and fragmentation of arterial elastic fibers observed in atherosclerosis. Additionally, several epidemiological studies report that increased dietary intakes of silicon are associated with a reduced risk of coronary heart disease in humans (Schwarz et al., Lancet, i:454-457, 1977; Schwarz et al., Lancet, i:538-539, 1977; Bassler, Brit. Med. J., 1:919, 1978; Parr, Lancet, i:1087, 1980).
Studies in growing young rats and chicks show that severe dietary silicon deficiency results in abnormal bone and joint structures, apparently due to subnormal production of collagen and mucopolysaccharides (Carlisle, J. Nutr. 106:478-484, 1976; Carlisle, J. Nutr. 110:1046-1055, 1980). Silicon promotes the synthesis of collagen and mucopolysaccharides in vitro (Carlisle et al., Fed. Proc. 37:404, 1978; Carlisle et al., Fed. Proc. 39:787, 1980). The biochemical method by which silicon achieves this effect are unknown. Silicone has been shown to enhance bone mineral density. When an organosilicon compound (monomethyltrisilanol) was administered to postmenopausal women by injection at a dose of 50 mg twice weekly, femoral density increased significantly by an average of 4.7% over 14 months of administration (Eisinger et al., Magnesium Res. 6:247-249, 1993). In ovariectomized rats, oral orthosilicic acid slowed bone turnover and increased the bone formation rate (Hott et al., Calcif. Tissue Int. 53:174-179, 1993).
Bone and cartilage are dynamic tissues in both juvenile and adult animals. In bone, osteoclasts solubilize the hydroxyapatite bone matrix and degrade collagen, whereas osteoblasts concurrently rebuild bone through collagen synthesis and hydroxyapatite deposition. Analogously, chondrocytes in cartilage simultaneously degrade the collagen and proteoglycan matrix and resynthesize it. The impact of silicone on bone and cartilage formation in adult animal is essentially unknown. However, it is highly unlikely that the role of silicon in bone and cartilage metabolism is limited to juvenile animals.
The nutritional role of silicon is to support adequate synthesis of mucopolysaccharides, proteoglycans and collagen (Schwarz et al., Nature, 239:333-334, 1972; Carlisle, Science, 178:619-621, 1972; Carlisle, J. Nutr., 106:478-484, 1976; Schwarz, in Biochemistry of Silicon and Related Problems, Plenum Press, New York, 1978, pp. 207-230). Optimal silicon nutrition may promote production of protective HSPGs by endothelial cells.
Arginine, an essential amino acid, is the biosynthetic precursor for the nitric oxide (NO) produced by vascular endothelium (Moncada, New Engl. J. Med., 329:2002-2012, 1993). NO exerts vasodilatory, antiatherosclerotic and antithrombotic effects, and deficient endothelial production of NO may play a prominent pathogenic role in atherosclerosis, hypertension and diabetes (Calver et al., J. Hypertension, 10:1025-1031, 1992; Cooke et al., Arterioscler. Thromb. 14:653-655, 1994; Rubanyi, in: Cardiovascular Significance of Endothelium-Derived Vasoactive Factors, Futura Publishing Co. Inc., New York, 1991, pp. xi-xix). In some though not all clinical studies, parenteral or oral administration of arginine has enhanced vascular NO synthesis (Drexler et al., Lancet, 338:1546-1550, 1991). In animal models of hypertension, arginine supplementation has moderated the increase in blood pressure (Chen et al., J. Clin. Invest., 88:1559-1567, 1991; Laurant et al., Clin. Exp. Hyperten., 17:1009-1024, 1995). Thus, under at least some circumstances, arginine availability can be rate-limiting for NO production. A recently published clinical study indicates that oral arginine can enhance endothelium-dependent relaxation in hypercholesterolemic young people (Creager et al., J. Clin. Invest., 90:1248-1253, 1992; Clarkson et al., J. Clin. Invest., 97:1989-1994, 1996) which is indicative of increased efficiency of vascular NO production.
There is a constant need for therapeutic/prophylactic agents capable of preventing or retarding the progression of atherosclerosis and promoting the formation of bone and cartilage. The present invention addresses these needs.